Nine treatments of 1000 mL therapeutic phlebotomy in a subject with polycythemia: A case report

Abstract Large‐volume therapeutic phlebotomy is the mainstay of hemochromatosis treatment and offers an opportunity to investigate the hemodynamic changes during acute hypovolemia. An otherwise healthy 64‐year‐old male with hemochromatosis participated. On nine separate visits, 1000 mL therapeutic phlebotomy was performed. On one occasion, pre‐ and post‐phlebotomy orthostatic challenge with 27° reverse Trendelenburg position was administered. Mean arterial pressure, heart rate, and stroke volume were measured continuously during the procedures. The patient's tolerance to the interventions was continuously evaluated. The procedures were well tolerated by the patient. Mean arterial pressure was maintained during hemorrhage and following phlebotomy in both supine and reverse Trendelenburg positions, primarily through an increase in heart rate and systemic vascular resistance. The present study found that 1000 mL therapeutic phlebotomy in a patient with hemochromatosis may be acceptably and safely used to model hemorrhage. The approach demonstrates high clinical applicability and ethically robustness in comparison with volunteer studies.


| INTRODUCTION
Hemochromatosis is characterized by elevated hematocrit and hemoglobin.Increased mortality is largely owed to solid-organ iron deposition and hyperviscosity syndrome (Murphree et al., 2020).Therapeutic phlebotomy (TP) has the goal of normalizing the hematocrit and ameliorating potential complications (Sloop et al., 2015).
Acute hemorrhage is of clinical and research importance (Shah et al., 2023).The ethical and practical challenges of studying clinical acute hemorrhage have resulted in the development of lower body negative pressure (LBNP) to reversibly simulate central hypovolemia (Goswami et al., 2019).Although LBNP has been found to model the hemodynamics of actual blood loss (Johnson et al., 2014), TP has advantages compared to LBNP.First, blood loss is real rather than a redistribution of blood to the lower extremities.Second, the hemochromatosis patient population requiring phlebotomy better reflects the clinical population, since it consists of individuals aged over 40 rather than the healthy volunteers commonly used in LBNP studies.
Volunteers undergoing LBNP studies do so for presumably do altruistic reasons.In TP, patients´ experimentation is secondary to their clinical treatment, rather than the principale propositum.Section 17 of the WMA Declaration of Helsinki (World Medical Association, 2013) states that "All medical research involving human subjects must be preceded by careful assessment of predictable risks and burdens to them."A study investigating blood loss during TP in a hemochromatosis patient will cause minimal extra burdens, conversely in a volunteer any procedure may be considered burdensome.Thus, hemochromatosis patients can be considered to have limited added burden associated with the research and receive the benefit of treatment, while volunteers have considerable burdens and no benefits.
We hypothesized that study of the hemodynamic effects of acute blood loss in therapeutic phlebotomy may offer an ethical alternative and greater clinical applicability than LBNP studies in healthy volunteers.This historical case series aims to determine if acute hemorrhage, including an orthostatic challenge, may be adequately modeled in a hemochromatosis patient requiring repeated therapeutic phlebotomy.

| METHODS
Following approval by the Regional Ethics Committee (RKMFII ref S-96203) and informed written consent, an otherwise healthy Caucasian 64-year-old man with homozygous hemochromatosis requiring repeated phlebotomy was recruited.Clinical examination and echocardiogram revealed a functionally normal heart.
The tolerability of rapid hemorrhage was assessed by titrating the volume of phlebotomy, from 500 to 1000 mL over three visits.1000 mL blood loss was well tolerated by the subject, and this volume was subsequently used.
Between 1997 and 2003, the hemodynamic measures associated with clinically indicated 1000 mL phlebotomy were investigated on nine instances.Each intervention was followed with an infusion of 1000 mL of Ringer acetate.
Following local anesthetic, the femoral vein was catheterized.Cardiovascular measurements were continuously recorded.Using a 50 mL syringe and three-way tap, 1000 mL blood was aspirated over a period of 11-15 min (mean 742 s, range 659-910 s).
At the participant's suggestion and with ethics committee approval, we exacerbated the post TP hemodynamic stress with reverse Trendelenburg position (RTP) (Matzen, 1995).Comparing RTP responses before and after acute blood loss has clinical implications for hypovolemic patients in head up positions, for example, on the operating table.One episode of tilt table testing was conducted.Cardiovascular measurements were recorded during the supine (120 s) and RTP (27° head up, 120 s) positions; then, 1000 mL phlebotomy was performed followed by measurements in the supine and RTP positions.
Three lead ECG heart rate (HR) and the ultrasound maximum velocity signal were interfaced to a personal computer.The diameter of the aortic ring was determined (CFM-750, GE Vingmed Ultrasound, Horten, Norway) and used to calculate the aortic valvar root area.SV was calculated by integration of the recorded maximum velocity during each R-R cycle and the area of the aortic root (Eriksen & Walløe, 1990).Cardiac output (CO) was calculated as HR × SV.
Blood pressure was continuously measured using the volume-clamp method (Finapres BP monitor; Ohmeda, Madison, WI USA) (Imholz et al., 1998).Mean arterial pressure (MAP) was calculated by numerical integration.Systemic vascular resistance (SVR) was calculated as MAP/CO.
Beat to beat values were calculated for all variables and gated by the ECG R-wave.The supine position was defined as an angle of <1° from the horizontal plane and RTP as an angle >25°.
JMP® Pro 17.0.0(JMP Statistical Discovery LLC) was used for statistical analysis.Data are medians and interquartile ranges (IQR) if not otherwise stated.Wilcoxon signed rank test was used for paired comparisons pre-post blood loss.Results were interpreted as statistically significant with a p value < 0.05.
The CARE checklist was used in the preparation of this article (Riley et al., 2017).

| RESULTS
The procedures were well tolerated by the patient.

| Central hemodynamic responses
HR and blood pressure data were available from nine episodes of phlebotomy.Concurrent ultrasound measurements were available from six of these episodes.
Increasing blood loss was associated with a marked decrease in SV, counteracted by a moderate increase in HR and marked increase in SVR.Consequently, CO declined while MAP and systolic arterial pressure was maintained at pre-intervention levels during hemorrhage through an increase in HR and SVR (Figure 1).Absolute and percentage changes in cardiovascular variables after 1000 mL blood withdrawal are presented in Table 1.1000 mL blood loss.Compared with RTP phlebotomy, RTP post-phlebotomy induced an accentuated HR increase, slightly less further declines in SV and CO, similar increase in SVR, and a smaller increase in MAP (Table 2).

| DISCUSSION
In this study, 1000 mL acute blood loss was well tolerated, and the hemodynamic compensation could be characterized in detail.MAP remained within the baseline range in the supine position and increased during RTP, while SV decreased.The SV related decrease in CO was compensated for by an increase in HR and SVR, as previously described (Kirkman & Watts, 2014).Hemodynamic responses to RTP differed according to volume state (prevs.post-phlebotomy).The mechanisms by which our subject compensated to such a high degree may include (1) conditioning by exposure to repeated phlebotomy, (2) a high hematocrit, which is the major determinant of blood viscosity and consequently elevated SVR (Pearson et al., 1980).Visual inspection of data did not reveal time trends.In this study, hematocrit should be considered a relatively constant parameter since there was little time for autologous expansion of the plasma volume to occur following phlebotomy.
Having the blood loss occur over 11-15 min increases this study's applicability to clinical scenarios in which there is rapid bleeding.The subject's age (64 years) further increases the clinical applicability.There is an increased prevalence and risk of trauma in the elderly (Adams & Holcomb, 2015), who also more frequently use anticoagulant therapy.Elderly patients may respond differently from younger patients (Kuchel et al., 1992) and warrant targeted research.

| CONCLUSION
The present study found that 1000 mL therapeutic phlebotomy in a patient with hemochromatosis may be acceptably and safely used to model hemorrhage.The approach demonstrates high clinical applicability and ethically robustness in comparison with volunteer studies.